Discussion Highlights Merits, Limitations of Small Trials

Closer examination of PRAMI, WOEST sheds light on clinical trial design

Clinical decisions such as how to optimally treat multivessel disease or determine the best antiplatelet therapy regimen require several studies to agree on standard-of-care practices. During a didactic session at TCT 2015, two presentations focused on the PRAMI and WOEST trials — which enrolled 465 and 573 patients, respectively — and  questioned how much faith in general physicians should put in small trials.

The PRAMI trial, published in the New England Journal of Medicine in 2013, showed that STEMI patients with multivessel disease fare substantially better when they undergo immediate PCI of both the infarct-related artery and other diseased arteries. The study was stopped early when a clear advantage was observed for the preventive strategy.

The WOEST study, published in the Lancet in 2013, demonstrated higher rates of total TIMI bleeding and death with standard dual antiplatelet therapy compared with clopidogrel alone among patients taking oral anticoagulants while undergoing PCI. Thus, eliminating aspirin and continuing clopidogrel appeared to be a viable option.

A trialist viewpoint 

John A. Bittl, MD, of Munroe Regional Medical Center, Ocala, Fla., examined the studies from a trialist and guidelines perspective.

“PRAMI increased our awareness that observational studies are confounded,” Bittl said. “We knew that but … we can’t ignore the observational data and Bayesian analyses.”

Bayesian analyses, he continued, allow for “studies of different designs to be analyzed together and [generalize] results for the STEMI population by including evidence from randomized controlled trials and observational studies.”

PRAMI was a “milestone,” according to Bittl. With the publication of the CvLPRIT and DANAMI-3 studies, there is now “a significant evidence base to consider general changes in clinical practice,” but we still “cannot define the optimal timing of noninfarct PCI.”

With WOEST, Bittl said, the apparent discrepancy between that study and others was due to differences in endpoint definitions. Specifically, WOEST used “a broad definition of bleeding,” whereas others focused only on major bleeding.

A clinician viewpoint

Eric R. Bates, MD, of the University of Michigan Medical Center, Ann Arbor, Mich., spoke from a clinician’s standpoint.

Based on PRAMI and other trials, he said, multivessel PCI is “feasible and probably safe,” but “we have to be careful that we only do it in patients where PCI would otherwise meet appropriate use criteria.” Importantly, patients with chronic total occlusions or complex lesions would best be treated in a staged setting, Bates added.

Unfortunately, he said, none of the trials currently in progress are going to be able to definitively answer the question of whether “more complete revascularization is [better than] single-vessel revascularization and whether it should be anatomy- or ischemia-guided or done in one vs. two settings,” he said.

The results of WOEST, Bates said, are “paradoxical,” but the bleeding advantage observed by eliminating aspirin cannot be denied. “Double antithrombotic therapy is feasible and safer than triple therapy,” he added, but noted that physicians need to do a better job educating patients to avoid NSAIDs.

“Importantly, based on the guidelines, the proper timing of transition from triple therapy to double therapy is unclear and should be individualized,” Bates said.

Quality vs. quantity

Panelist Sanjay Kaul, MD, of Cedars-Sinai Medical Center, Los Angeles, Calif., said he is concerned about the “implausibly large treatment effects” seen in small single-center trials. These trials are “seldom replicable and not reliable” and would not meet the FDA’s criteria for independent substantiation, he said.

“Small trials help us set the agenda for future investigation,” Kaul said, “but quality vs. quantity of evidence is very shaky. … It’s the quality and the quantity that will preclude drawing actionable inferences from these trials.”

Disclosures:

• Bates reports receiving consultant/honoraria/speakers fees from AstraZeneca.
• Bittl reports no relevant conflicts of interest.
• Kaul reports receiving consultant/honoraria/speakers fees from Amgen, AstraZeneca, Biotronik, Boehringer Ingelheim, Hospira, Sanofi-Aventis and The Medicines Company.